DLHex-DGJ, a novel derivative of 1-deoxygalactonojirimycin with pharmacological chaperone activity in human GM1-gangliosidosis fibroblasts

Fantur, Katrin; Hofer, Doris; Schitter, Georg; Steiner, Andreas; Pabst, Bettina M.; Wrodnigg, Tanja; Stütz, Arnold; Paschke, Eduard

doi:10.1016/j.ymgme.2010.03.019

Cited by 55 publications

(45 citation statements)

References 34 publications

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“…Different models exist for the force driving low pH dissociation, including protonation of the pharmacological chaperone, protonation of an active site residue, competition by excess substrate, etc. (Fan, 2003, 2008; Fantur et al, 2010; Jo et al, 2010; Suzuki et al, 2009). For lysosomal enzymes, the pH dependence of affinity of the PC is important, as the chaperone must dissociate from the active site at low pH for the enzyme to function.…”

Section: Resultsmentioning

confidence: 99%

The Molecular Basis of Pharmacological Chaperoning in Human α-Galactosidase

Guce

Clark

Rogich

et al. 2011

Chemistry & Biology

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Summary Fabry disease patients show a deficiency in the activity of the lysosomal enzyme α-galactosidase (α-GAL or α-Gal A). One proposed treatment for Fabry disease is pharmacological chaperone therapy, where a small molecule stabilizes the α-GAL protein, leading to increased enzymatic activity. Using enzyme kinetics, tryptophan fluorescence, circular dichroism, and proteolysis assays, we show that the pharmacological chaperones 1-deoxygalactonojirimycin (DGJ) and galactose stabilize the human α-GAL glycoprotein. Crystal structures of complexes of α-GAL and chaperones explain the molecular basis for the higher potency of DGJ over galactose. Using site directed mutagenesis, we show the higher potency of DGJ results from an ionic interaction with D170. We propose that protonation of D170 in acidic conditions leads to weaker binding of DGJ. The results establish a biochemical basis for pharmacological chaperone therapy applicable to other protein misfolding diseases.

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Section: Resultsmentioning

confidence: 99%

The Molecular Basis of Pharmacological Chaperoning in Human α-Galactosidase

Guce

Clark

Rogich

et al. 2011

Chemistry & Biology

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“…Note that the effects of NB-DNJ and AMP-DNJ on GBA are primarily seen in in vitro assays, not in cultured cells or in vivo. pharmacological basis for substrate reduction therapy in type 1 Gaucher disease (30), whereas at sub-inhibitory concentrations these compounds can act as chemical chaperones for mutant forms of GBA found in Gaucher disease, facilitating protein folding (31)(32)(33). Many of the imino sugars employed in substrate reduction and chemical chaperone therapies also inhibit GBA2 (9,34,35).…”

Section: Glucosylceramide (Glccer)mentioning

confidence: 99%

β-Glucosidase 2 (GBA2) Activity and Imino Sugar Pharmacology

Ridley

Thur

Shanahan

et al. 2013

Journal of Biological Chemistry

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Background: GBA2 and GBA are both ␤-glucosidases that degrade glucosylceramide. Results: Conduritol B epoxide inactivates both GBA and GBA2, whereas the imino sugar NB-DGJ selectively inhibits GBA2. Conclusion: NB-DGJ is a suitable reagent to distinguish GBA2 from GBA. Significance: This study redefines GBA2 activity, which is relevant for clinical GBA2 measurements and imino sugar pharmacology.

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“…Chaperone candidates for human b-gal were also explored in the derivatives of DGJ (taBle 2) [48][49][50]. Recently, Rigat et al reported that N-nonyl-DGJ (NN-DGJ) enhanced mutant b-gal activity in feline G M1 -gangliosidosis fibroblasts.…”

Section: Other Chaperone Candidates For Human B-galmentioning

confidence: 99%

“…Chaperones for Gaucher and Pompe diseases have also been tested in preclinical studies. In addition, synergetic effect of Yes (model mice) [32][33][34][35][36][38][39][40] DGJ, NB-DGJ R201C, R201H, R457Q ND [32] Galactose R442Q ND [72] DLHex-DGJ R201C, R201H, C230R, G428E ND [48] Fluorous iminoalditols R148S, R201C, D332N ND [49] NN-DNJ R201H, W509C, R483P (feline GLB1) ND [50] 6S-NBI-DGJ (MTD118) 24 out of 88 missense mutations (including I51T, R201C, G438E)…”

Section: Future Perspectivementioning

confidence: 99%

Candidate Molecules for Chemical Chaperone Therapy of G _M1 -Gangliosidosis

et al. 2013

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A growing body of evidence suggests that misfolding of a mutant protein followed by its aggregation or premature degradation in the endoplasmic reticulum is one of the main mechanisms that underlie inherited neurodegenerative diseases, including lysosomal storage diseases. Chemical or pharmacological chaperones are small molecules that bind to and stabilize mutant lysosomal enzyme proteins in the endoplasmic reticulum. A number of chaperone compounds for lysosomal hydrolases have been identified in the last decade. They have gained attention because they can be orally administrated, and also because they can penetrate the blood-brain barrier. In this article, we describe two chaperone candidates for the treatment of GM1-gangliosidosis. We also discuss the future direction of this strategy targeting other lysosomal storage diseases as well as protein misfolding diseases in general.

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DLHex-DGJ, a novel derivative of 1-deoxygalactonojirimycin with pharmacological chaperone activity in human GM1-gangliosidosis fibroblasts

Cited by 55 publications

References 34 publications

The Molecular Basis of Pharmacological Chaperoning in Human α-Galactosidase

The Molecular Basis of Pharmacological Chaperoning in Human α-Galactosidase

β-Glucosidase 2 (GBA2) Activity and Imino Sugar Pharmacology

Candidate Molecules for Chemical Chaperone Therapy of G _M1 -Gangliosidosis

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DLHex-DGJ, a novel derivative of 1-deoxygalactonojirimycin with pharmacological chaperone activity in human GM1-gangliosidosis fibroblasts

Cited by 55 publications

References 34 publications

The Molecular Basis of Pharmacological Chaperoning in Human α-Galactosidase

The Molecular Basis of Pharmacological Chaperoning in Human α-Galactosidase

β-Glucosidase 2 (GBA2) Activity and Imino Sugar Pharmacology

Candidate Molecules for Chemical Chaperone Therapy of G M1 -Gangliosidosis

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Product

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Candidate Molecules for Chemical Chaperone Therapy of G _M1 -Gangliosidosis